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The two main causes of pancytopenia in children with malignancies are:

1. Invasion or replacement of the bone marrow by malignant cells

2. Myelosuppression due to chemotherapeutic agents.

Blood component administration is an integral component of management. The risks associated with transfusions (Table 26-9) are:

1. Transfusion reactions (febrile and hemolytic reactions)

2. Development of alloimmunization and refractoriness

3. Transmission of infectious agents

4. Development of graft versus host disease (GVHD).

Transfusion reactions include:

1. Acute hemolytic transfusion reactions

2. Delayed hemolytic transfusion reactions

3. Febrile nonhemolytic transfusion reactions

4. Allergic reactions

5. Transfusion-related acute lung injury (TRALI).

Most hemolytic reactions are acute hemolytic transfusion reactions and result from blood group incompatibility (both major and minor red cell antigens) between the donor and the recipient. They can be prevented by thorough typing and cross-matching of all packed red cell transfusions. Acute hemolytic transfusion reactions present with fever, chills, back or abdominal pain, dark urine, pallor, bleeding, or shock during the

Table 26-9. Relative Risks of Transfusion Complications per Unit

Risk Risk ratio

Hepatitis C 1:1,600,000

HIV 1:1,900,000

Wrong blood in tube 1:1,000

Wrong recipient of auto unit 1:16,000

TRALI 1:5,000

Hemolysis from ABO-incompatible 1:10,000-46,000 plasma in an apheresis platelet

Abbreviation: TRALI, transfusion-related acute lung injury.

transfusion. Laboratory investigations show positive direct antiglobulin test, sphe-rocytes, decreased haptoglobin, hyperbilirubinemia, and hemoglobinuria. The transfusion should be stopped immediately. The unit and a sample of the patient's blood should be sent to the blood bank for investigation. The patient should be vigorously hydrated. Delayed hemolytic transfusion reactions occur 2-14 days after the transfusion. Patients present with low-grade fever, decreased hemoglobin, and jaundice.

Febrile reactions are almost always caused by sensitization to leukocyte antigens. They can be largely prevented by two measures:

1. Leukocyte-depleted products (usually through the use of leukocyte filters). Prestorage leukocyte filtration offers the most effective approach. Inflammatory cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor a [TNF-a]) secreted from leukocytes cannot be filtered by post-storage filtration and may still lead to febrile reactions.

2. Premedication of the recipient with Tylenol 10-15 mg/kg and Benadryl 1 mg/kg.

Allergic reactions are due to plasma proteins. Mild cutaneous hypersensitivity reactions (itching, rash, redness) respond to antihistamines. Severe allergic reactions are often due to development of anti-IgA in IgA-deficient patients. Patients may require epinephrine and parenteral steroids.

Transfusion-related acute lung injury occurs within 4-6 hours of transfusions. Leukoagglutinins in the donor blood interact with recipient white cells and lead to sequestration of the white cell complexes in the pulmonary vasculature. This results in increased vascular permeability and exudation of fluid and protein into the alveoli. The clinical picture of TRALI resembles adult respiratory distress syndrome. Patients present with dyspnea, hypoxia, fever, and noncardiogenic pulmonary edema. Treatment is supportive. Table 26-10 lists the clinical benefits from using leukoreduced blood products.

Alloimmunization and Refractoriness

To some extent, all transfusion recipients become sensitized to foreign leukocyte antigens. However, the use of leukocyte filters helps to prevent this problem.

The problem of refractoriness applies particularly to platelet transfusions. Patients who are refractory show no rise or significantly less than the expected rise in platelet count following a platelet transfusion. In some patients, refractoriness occurs much sooner than in others. Specific factors affecting platelet survival will be discussed in the section on platelet transfusions.

Transmission of Infectious Agents

The agents that can be transmitted by transfusions are viruses, including cytomegalovirus (CMV), hepatitis, and human immunodeficiency virus (HIV),

Table 26-10. Clinical Benefits from Using Leukoreduced (LR) Blood Products

Prevention of recurrent febrile nonhemolytic transfusion reactions

Prevention of primary HLA-alloimmunization and resulting complications, including platelet refractoriness Prevention of transfusion-transmitted cytomegalovirus infection in at-risk patients Reduction of prion (vCJD) transmission

Reduction of transmission of other leukotropic viruses (HTLV I-II and EBV)

Reduction of viral reactivation

Reduction of parasitic or bacterial infections

Reduction of transfusion-related acute lung injury

Abbreviation: CJD, Creutzfeldt-Jakob disease

(Table 26-11) bacteria, and protozoa. Careful donor selection and improvements in screening and blood product testing have largely eliminated this problem. The other infectious risk is bacterial contamination of the donor units of blood. Infection is most commonly due to Yersinia enterocolitica and other gram-negative organisms. Platelet units are most commonly contaminated with S. aureus, Klebsiella pneumoniae, Serratia marcenses, and Staphylococcus epidermidis. Parasitic infections that can be transmitted through blood transfusion are malaria, Chagas disease, and Babesia.

Donated blood is screened for hepatitis B and C and HIV. Positive units are discarded. CMV may be transmitted via CMV antibody-positive blood. Eighty-five percent of the population is positive for CMV antibodies. It is, therefore, impossible to discard all CMV-positive units. Because of the high risk of CMV interstitial pneumonitis in severely immunocompromised patients, it is recommended that patients who will be undergoing allogeneic stem cell transplantation and who are CMV antibody negative receive CMV antibody-negative products. Patients who will not be undergoing transplant or transplant patients who are already CMV positive can receive CMV-positive, leuko-depleted products. Leuko-depletion reduces the risk of CMV and, in theory, Creutzfeldt-Jakob disease.

Graft versus Host Disease

GVHD has been observed to arise 4-30 days after the administration of nonirradi-ated blood products to immunocompromised patients. It results from viable donor precursor cells or stem cells engrafting in the immunocompromised host's marrow. The clinical manifestations are fever, erythematous maculopapular skin rash, anorexia, nausea, vomiting, diarrhea, elevated liver enzymes, and hyperbilirubine-mia. A very high morbidity and mortality rate is associated with transfusion-acquired GVHD. Measures to prevent GVHD include irradiating all blood products with 2500 cGy and depleting the blood products of leukocytes.

General Guidelines

All oncology patients should receive leukocyte-filtered, irradiated blood products. CMV-negative products should be used according to the previously mentioned guidelines.

Red Cell Transfusions

Causes of anemia in cancer patients in children include:

1. Replacement of the bone marrow with malignant cells

2. Chemotherapy-induced myelosuppression

3. Anemia of inflammation

Table 26-11. Risk Estimates of Viral Transmission by Transfusion

Virus/infection

Estimated risk in 2GG2

Human immunodeficiency virus (HIV)

1:2,135,000

Hepatitis C (HCV)

1:1,935,000

Hepatitis B (HBV)

1:1,205,000

Human T-cell lymphotropic virus (HTLV-I/II)

1:641,000

From Jamali F, Ness PM. Infectious complications. In: Hillyer CD, Strauss RG, Luban NLC, editors. Handbook of Pediatric Transfusion Medicine. San Diego: Elsevier Academic Press, 2004;329-39.

From Jamali F, Ness PM. Infectious complications. In: Hillyer CD, Strauss RG, Luban NLC, editors. Handbook of Pediatric Transfusion Medicine. San Diego: Elsevier Academic Press, 2004;329-39.

4. Blood loss due to thrombocytopenia

5. Iatrogenic blood loss

6. Hemolysis.

Packed red cell transfusions are indicated for patients whose hemoglobin is less than 8 g/dL or those whose hemoglobin is greater than 8 g/dL but who are cardio-vascularly unstable and have respiratory failure or bleeding.

Patients should receive 10-15 mL/kg of packed red cells over 3 hours. Each transfusion should be completed within 4 hours after the unit or aliquot has been started.

Patients who are profoundly anemic (Hgb, <5 g/dL) should be transfused at a slower rate (3-5 mL packed red cells/kg over 3-4 hours) with careful monitoring of vital signs. Repeat transfusions can be given.

The expected increment can be estimated as follows: 1 mL/kg of packed red cells increases the hematocrit by 1%.

Platelet Transfusions

The causes of thrombocytopenia in children who have cancer are:

1. Decreased production

2. Increased destruction

3. Hypersplenism

4. Consumption due to brisk bleeding or massive transfusion.

Serious bleeding episodes and spontaneous bleeding occur when the count is below 15,000-20,000/mm3. For this reason, platelet transfusions are given when:

1. The platelet count is less than 15,000-20,000/mm3.

2. The platelet count is greater than 20,000/mm3, but the patient is bleeding (e.g., prolonged epistaxis, GI bleeding, or CNS bleeding).

3. The patient is scheduled for an invasive procedure and the platelet count is less than 50,000/mm3.

Platelets are collected in two ways:

1. Platelets are collected from units of routinely donated whole blood and pooled (random-donor) platelets; 1 unit of random-donor platelets has 5-10 x 1010 platelets.

2. Platelet concentrates can be collected from a single donor by platelet apheresis; 1 unit of single-donor platelets has 3-6 x 1011 platelets (roughly equivalent to 6 units of random donor platelets).

The dose of platelets given per transfusion is 1 unit random-donor platelets/10 kg or 1 unit single-donor platelets/50 kg. Apheresis units may be divided for smaller patients. Use ABO-type-specific platelets. The expected platelet increment can be calculated by corrected platelet count index (CCI) as follows:

Post-transfusion platelet count - pretransfusion platelet count x body surface area

Number of platelets transfused (x1011)

One unit of random-donor platelets per 10 kg of body weight should increase the platelet count by 40,000-50,000/mm3 within 1 hour after the infusion. In the average-sized adolescent or adult, 6 units of platelet concentrates or 1 single-donor apheresis unit will increase the platelet count by 50,000/mm3 or greater. If the post-transfusion platelet count is below the expected count, the patient is refractory. Table 26-12 lists the factors leading to decreased platelet transfusion response and approaches to platelet refractoriness.

Table 26-12. Factors Leading to Decreased Platelet Transfusion Response

Age of transfused platelets Washing platelets Fever, infection

Disseminated intravascular coagulation Graft versus host disease Hepatosplenomegaly, hypersplenism Alloantibodies/autoantibodies Massive blood loss

Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura

(platelet transfusions discouraged/contraindicated) Necrotizing enterocolitis

Medications (amphotericin, vancomycin, ciprofloxacin)

Approaches to platelet refractoriness

Transfuse ABO identical platelets Use fresh platelets HLA-Matched platelets Cross-matched platelets

Intravenous gammaglobulin 1 g/kg prior to transfusion

Plasmapheresis

Corticosteroids

Other measures to prevent bleeding in patients with severe thrombocytopenia include:

1. Avoid invasive procedures: nasogastric tube or urinary catheter insertion, rectal examination, intramuscular injections, deep venipunctures.

2. Apply local pressure for wounds and epistaxis.

3. Avoid aspirin and other drugs that interfere in platelet function (Chapter 10).

4. Epsilon-aminocaproic acid or prednisone can be used as adjunct treatment in bleeding patients.

5. Estrogen or high-dose birth control pills may be used for menometrorrhagia. Granulocyte Transfusions

Neutropenia (ANC <1000/mm3) and severe neutropenia (ANC <500/mm3) commonly occur in patients on chemotherapy. Severe neutropenia greatly increases the risk for overwhelming sepsis and for invasive fungal infections. Most neutropenic patients are treated with G-CSF to shorten the period of neutropenia (see later section titled Hematopoietic Growth Factors). Occasionally, however, patients are treated with granulocyte transfusions.

Indications

1. Serious bacterial (particularly gram-negative) or fungal infection with persistent (48 hours or more) positive cultures despite appropriate antibiotic coverage in severely neutropenic patients (ANC <200/mm3).

2. The ANC is not expected to increase to more than 500/mm3 for several days.

3. Prolonged survival of the patient is reasonably expected if the infection is controlled.

4. In addition, patients with severe granulocyte dysfunction (e.g., chronic granu-lomatous disease) who have severe infection.

Risks

1. CMV infection

2. Graft versus host disease

3. Respiratory distress with pulmonary infiltrates (particularly in patients concurrently receiving amphotericin)

4. Alloimmunization

5. Hemolytic reactions.

Precautions to Be Observed

1. Use granulocytes from an ABO-Rh compatible donor.

2. If the patient is on amphotericin, leave 4-6 hours between amphotericin and granulocyte transfusion.

3. Do not administer with a leukocyte-depleting filter.

4. Administer granulocytes as soon as possible after collection to maximize effectiveness. If not used immediately, store at room temperature.

5. Premedicate with diphenhydramine and hydrocortisone.

6. Granulocytes are always irradiated to prevent transfusion-associated GVHD.

Dose and Duration

1. The dose is usually greater than 0.75-1.0 x 1010 granulocytes

2. The transfusion is administered through a 170-pm filter at a rate of 150 mL/m2/hour.

3. Granulocytes are usually administered for 5-7 days or until the ANC has risen to more than 500/mm3. (Transfused granulocytes have a half-life of 6-10 hours and do not increase the ANC.)

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